CN116832015A - Agomelatine film agent for oral mucosa administration and preparation method thereof - Google Patents

Agomelatine film agent for oral mucosa administration and preparation method thereof Download PDF

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CN116832015A
CN116832015A CN202311054277.8A CN202311054277A CN116832015A CN 116832015 A CN116832015 A CN 116832015A CN 202311054277 A CN202311054277 A CN 202311054277A CN 116832015 A CN116832015 A CN 116832015A
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agomelatine
film
polyethylene glycol
adhesive layer
weight
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叶英
朱海健
凌榕镔
高周锷
阿维纳什·辛格
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Lipin Pharmaceutical Xiamen Co ltd
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Lipin Pharmaceutical Xiamen Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

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Abstract

The application discloses an agomelatine film agent for oral mucosa administration and a preparation method thereof, and provides a pharmaceutical preparation for agomelatine administration through oral mucosa. The film agent is a double-layer film agent consisting of a medicine-containing adhesive layer and a medicine-free backing layer, and the double-layer film structure ensures that the medicine has good bioavailability and good taste. The drug-containing adhesive layer of the agomelatine film agent prepared by the application comprises 0.1-40% (w/w) of agomelatine as an active ingredient or pharmaceutically acceptable salt thereof, 50-98% (w/w) of one or more film-forming materials, 0.5-20% (w/w) of one or more oil phases and 0.5-17% (w/w) of one or more surfactants. The backing layer contains 60-100% (w/w) of one or more film forming materials.

Description

Agomelatine film agent for oral mucosa administration and preparation method thereof
Technical Field
The application relates to a medicinal preparation in the field of medicines, in particular to a medicinal preparation for releasing agomelatine through oral mucosa in a film form and a preparation method thereof.
Background
Agomelatine is the first global melatonin receptor agonist antidepressant drug developed and marketed by the company Shi Weiya in france in 2009 and is another heavy weight antipsychotic drug. The medicament is a melatonin receptor (MT 1 and MT 2) agonist and a 5-hydroxytryptamine 2C (5-HT 2C) receptor antagonist, and the biological rhythm of the disturbance of a patient suffering from depression is recovered and synchronized mainly through the synergistic effect of the two, so that the antidepressant effect is realized. The agomelatine has the advantages of quick response, antidepressant, anxiolytic, sleep rhythm regulation and biological clock regulation, can improve the night sleep condition under the condition of not influencing the daytime biological rhythm, has fewer adverse reactions compared with other antidepressant drugs, has higher safety and no drug withdrawal reaction, and provides a new method for clinically treating MDD (major depressive disorder).
Agomelatine is currently marketed in the form of a tablet of only ordinary size, 25mg. The clinical efficacy is definite, but agomelatine tablets still have some drawbacks that severely limit their clinical application. First, agomelatine oral tablets have very low bioavailability (< 5%) due to the severe first pass effect of agomelatine. Meanwhile, the variation coefficient of the AUC of agomelatine is about 100% -150%, the variation among individuals (104%) is a main source, but the variation among individuals (157%) is also very large. Secondly, agomelatine has obvious hepatotoxicity, and can cause reversible transaminase increase of partial patients clinically, namely, the hepatotoxicity is high, and liver function monitoring is needed in clinical use.
Agomelatine tablets have low oral bioavailability, large AUC variation (100% -150%), and significant hepatotoxicity, and all patients should be examined for liver function at the time of initial treatment, and periodic assays at 6 weeks (at the end of acute phase treatment), 12 weeks and 24 weeks (at the end of maintenance treatment) are recommended, and the prior art drawbacks have affected clinical and patient safety.
Thus, in view of the problems of the prior art, there is a clinical need for a new pharmaceutical composition for delivering agomelatine to improve the bioavailability of agomelatine and reduce hepatotoxicity.
Disclosure of Invention
The present application finds a pharmaceutical composition suitable for administration via the oral mucosal route with improved bioavailability. The agomelatine film agent disclosed by the application is adhered to a cheek mucous membrane or a sublingual mucous membrane, can be disintegrated or dissolved within a few minutes, is directly absorbed through the cheek mucous membrane or the sublingual mucous membrane and enters into a jugular vein, so that the degradation of the gastrointestinal tract and the first pass effect of the liver are avoided, and the bioavailability of the agomelatine is obviously high, namely the Yu Age-melatine oral tablet.
The epithelial tissues of the oral mucosa (such as buccal mucosa, sublingual mucosa and the like) are not keratinized, the permeability is good, and the abundant blood vessels are directly connected with the jugular vein, thus providing a foundation for the absorption of medicines. The agomelatine film agent disclosed by the application can promote the absorption of agomelatine in oral mucosa and improve the bioavailability of agomelatine. The agomelatine film agent can realize the absorption curve and the peak blood concentration required by agomelatine and provide good bioavailability. The agomelatine film agent is suitable for delivering agomelatine through oral mucosa, and the bioavailability of the agomelatine film agent can reach 8-51 times of that of an agomelatine oral tablet.
According to literature reports, agomelatine has stronger hepatotoxicity when orally administered, and liver functions are strictly detected in clinical use. Currently marketed agomelatine tablets are administered at a dose of 25 mg/day, with a large oral dose, possibly causing some impairment of the liver function of the patient. Compared with a commercially available oral tablet, the agomelatine film agent for oral mucosa administration provided by the application has the advantages that the bioavailability is greatly improved, the same therapeutic effect as that of the tablet can be obtained under the condition of taking lower dose of agomelatine, and the risk of liver injury is reduced.
The application provides an agomelatine film agent, wherein an active ingredient agomelatine is in an amorphous form so as to improve the dissolution rate of a drug in an oral cavity. The agomelatine in the film agent in amorphous form can be released and absorbed rapidly after administration, and can act more rapidly.
Agomelatine has a strong irritation to the tongue in the oral cavity, and agomelatine diffused into the oral cavity during transmucosal administration causes irritation to the tongue of a patient resulting in patient compliance problems. The agomelatine film agent is of a double-layer film structure, and the double-layer film is provided with a drug-containing adhesive layer containing agomelatine and a back lining layer without drugs. The back lining layer can effectively prevent the medicine from diffusing into the oral cavity, so that the irritation of the medicine to the tongue is avoided, and the use compliance of patients is obviously improved.
The agomelatine film agent of the application reduces the peak plasma concentration (T) compared with the agomelatine oral tablet by applying the film agent to the oral mucosa (such as buccal film, sublingual mucosa and the like) of a subject, and the agomelatine is absorbed into blood through the oral mucosa max ) Is a time of (a) to be used. In addition, agomelatine according to the present application is absorbed into the blood through the oral mucosa, so that the administration is not affected by food.
The agomelatine film agent disclosed by the application has a double-layer film structure and comprises a drug-containing adhesive layer and a backing layer. The drug-containing adhesive layer comprises 0.1-40% of agomelatine in an amorphous state or pharmaceutically acceptable salt thereof, 50-98% of a first film forming material, 0.5-20% of an oil phase and 0.5-17% of a surfactant. Agomelatine is in an amorphous state in the drug-containing adhesive layer.
As used herein, a "pharmaceutically acceptable salt" is a salt that retains the desired biological activity of the parent compound and does not impart undesirable toxicological effects.
"about" as used herein means + -10% of the value recited.
Unless otherwise indicated, "%" in the present application refers to weight percent (w/w).
The active ingredient in the pharmaceutical composition is agomelatine or pharmaceutically acceptable salt thereof, such as agomelatine iodized salt, such as agomelatine hydroiodide, agomelatine hemitriiodide, agomelatine iodine hemitriiodide, agomelatine phosphate, agomelatine bisulfate, agomelatine mesylate or agomelatine besylate, and the like. The amount of agomelatine in the drug-containing adhesive layer is 0.1-10mg, preferably 0.1-5mg, 0.3-10mg, 0.3-5mg or 0.5-3mg. The weight percentage of agomelatine in the drug layer is generally 0.1-40% w/w, preferably 0.5-30% or 0.5-25% w/w.
The film forming material selected for the drug-containing adhesive layer is one or more of Hypromellose (HPMC), hypromellose (HPC), polyvinyl alcohol polyethylene glycol copolymer (PVA-PEG), polyvinyl alcohol (PVA), povidone (PVP) and polyethylene oxide (PEO), and the film forming material has good compatibility with agomelatine, provides high enough drug carrying capacity, and forms a film agent with good film forming property and flexibility, and can enable the agomelatine to keep an amorphous state in the film for a long time without crystallization. The proportion of film-forming material in the drug-carrying layer is generally 50-98% w/w, preferably 70-95% w/w or 80-95% w/w.
The oil phase of the drug-containing adhesive layer is one or more of propylene glycol dicaprate, glycerol monolinoleate, glycerol monooleate, diethylene glycol monoethyl ether, oleoyl polyoxyethylene glyceride, propylene glycol laurate, polyglycerol-4 oleate, isooctyl palmitate, polyethylene glycol cetostearyl ether and polyglycerol-3-diisostearate. The proportion of oil phase in the drug-carrying layer is generally 0.5-25% w/w, preferably 1-20% w/w or 1-15% w/w.
The surfactant selected for the drug-containing adhesive layer is one or more of lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride, oleic acid polyethylene glycol glyceride, linoleic acid polyethylene glycol glyceride, sodium dodecyl sulfate, monocaprylic acid capric acid glyceride, polyethylene glycol-32 stearate, caprylic acid capric acid polyethylene glycol glyceride and 15-hydroxystearic acid polyethylene glycol ester. The proportion of oil phase in the drug-carrying layer is generally 0.5-17% w/w, preferably 1-15% w/w or 1-10% w/w.
The drug-containing adhesive layer of the agomelatine film of the present application contains one or more oil phases and a surfactant (emulsifier) which provides a self-emulsifying drug delivery system. Self-emulsifying drug delivery systems are commonly used to deliver hydrophobic drugs to increase the bioavailability of water insoluble drugs. In self-emulsifying drug delivery systems, the drug spontaneously forms an emulsion with gentle agitation in the aqueous phase. The agomelatine film agent has good water solubility, and the film can be completely dissolved in water within 5 minutes and self-emulsified to form agomelatine microemulsion. The agomelatine film has good absorption curve, blood concentration and good bioavailability.
The speed of drug absorption by and time of adhesion to the oral mucosa can affect bioavailability, and the adhesive in the drug-containing adhesive layer can cause the film to adhere to the mucosa until completely dissolved. In one embodiment, the agomelatine film further comprises one or more adhesive agents in the drug-containing adhesive layer, the adhesive agents being capable of improving the adhesion of the drug-carrying layer without affecting agomelatine dissolution or reducing agomelatine bioavailability. Binders suitable for use in the present application include one or more materials such as hypromellose, hydroxypropyl cellulose, povidone, polyglutamic acid, polycarbophil, carbomer, dextran sulfate, chondroitin sulfate, sodium carboxymethyl cellulose, and the like.
The backing layer of the agomelatine film agent is made of one or more of Hypromellose (HPMC), hypromellose acetate succinate (HPMCAS), cellulose Acetate Phthalate (CAP), hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), hypromellose phthalate (HPMCP) and polyvinyl alcohol phthalate (PVAP). The film-forming material has a good barrier effect on agomelatine, and can effectively prevent agomelatine in the drug-containing adhesive layer from diffusing into the oral cavity. The amount of film forming material in the backing layer is 60-100% w/w, preferably 70-100% w/w or 80-100% w/w, resulting in a backing film having good flexibility.
When the thickness of the backing layer is more than or equal to 10 mu m and less than or equal to 60 mu m, the irritation of the medicine is obviously reduced. When the backing layer has a thickness of <10 μm, the irritation masking effect is poor. When the backing layer thickness is >60 μm, the release rate of the drug is affected. The backing layer preferably has a thickness of 10-60 μm. More preferably 10 to 40. Mu.m.
In one embodiment, one or more flavoring agents may be added independently to the medicated adhesive layer and/or the backing layer to enhance the mouthfeel of the drug. Flavoring agents suitable for use in the drug-containing adhesive and backing layers include, but are not limited to, sucrose, dextrose, sodium saccharin, fructose, xylitol, stevioside, aspartame, sucralose, neotame and acesulfame potassium, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, grape flavor. The amount of flavoring agent in the composition is 0.01-5%, preferably about 0.05-2% (w/w) in the medicated adhesive layer and 0-5% w/w in the backing layer. Flavoring agents added to the film may improve the taste of the film and provide good mouthfeel, and may increase patient compliance.
One or more colorants, such as food, pharmaceutical (FD & C) or pharmaceutical (D & C) colorants, may be added to the drug-loaded layer and/or the backing layer.
The application provides agomelatine film agents with high bioavailability. After the medicine is dissolved on the oral mucosa, the medicine can be self-emulsified to form microemulsion, and the permeation and absorption of the medicine are promoted. The film agent has a double-layer film structure; its backing layer prevents the drug from diffusing directly into the oral cavity and reduces the irritation of the drug. The agomelatine film disclosed by the application is uniform in appearance, uniform in thickness, uniform in color and luster and good in drug stability, and can be used for avoiding the first pass effect of a drug through oral mucosa administration, so that the bioavailability of agomelatine is obviously improved.
The agomelatine film of the present application is absorbed through the oral mucosa and into the blood, and is rapidly absorbed, compared with oral tablets in beagle animal experiments (T max :0.75 h), shortens the peak time (T) of blood drug solubility max : 0.33-0.5 h) and can accelerate the onset of action.
The application also provides a method for preparing the agomelatine bilayer membrane, which comprises the following steps: (a) a medicated adhesive layer: dissolving agomelatine or acceptable salt thereof, one or more first film forming materials, one or more oil phases and one or more surfactants in a first solvent to prepare a film forming solution containing medicines; (b) Uniformly coating and drying the film-forming solution containing the medicine to form a film, thereby obtaining a medicine-containing adhesive layer; (c) a backing layer: dissolving one or more second film-forming materials in a second solvent; (d) Uniformly coating the film forming solution of the backing layer on the prepared medicine-containing adhesive layer, and drying to obtain a double-layer film; (e) And stripping the dried bilayer film from the substrate to obtain the agomelatine film agent.
Agomelatine is insoluble in water, and the concentration of the first organic solvent-containing aqueous solution selected in (a) is 40.0% -100.0% in order to promote the dissolution of the crude drug and improve the content uniformity of the drug.
In the above preparation steps (a) and (c), flavoring agents and coloring agents may be added to the solution to improve taste and identity.
The drying temperature used in the above preparation steps (b) and (d) is 40 to 100 ℃, preferably 60 to 90 ℃.
According to the preparation method disclosed by the application, the agomelatine exists in an amorphous form in the drug-containing adhesive layer, so that the film can generate a relatively fast dissolution rate, and the bioavailability of the agomelatine is improved.
The base material used in the film coating and drying process is polyethylene terephthalate (PET), polypropylene resin (PP), polymethylpentene resin (TPX), or the like.
After step (e), the bilayer film may be cut to the appropriate size and shape and then further packaged.
The agomelatine film agent of the application is about 1-4cm long and about 1-4cm wide; preferably about 1-3cm in length and about 1-3cm in width. .
The application provides a method for administration of agomelatine through oral mucosa or sublingual mucosa, which is used for treating mental diseases such as depression, insomnia and the like.
The oral mucosa administration preparation prepared by the application is used for mammals, such as human beings, horses, dogs and cats. Treatment of humans is optimal.
Detailed Description
The present application will be described in further detail with reference to examples. It should be noted that the following description is merely illustrative of the technical solutions claimed by the present application, and is not meant to limit any of these technical solutions. The scope of the application is defined by the appended claims.
Example 1: agomelatine film agent (Crystal form film)
The present example tested an agomelatine crystalline form film, and the prescription and preparation method was performed as follows:
prescription:
the preparation process comprises the following steps:
dissolving/dispersing agomelatine in a solvent with continuous stirring;
adding other excipients and continuing stirring until a homogeneous mixture is formed;
vacuumizing/standing for defoaming;
uniformly coating the defoamed film forming liquid on a substrate;
drying at a temperature of about 60 ℃ to 90 ℃ to form a film;
after film formation, the film is cut to the appropriate size, shape, and filled into a pouch or an appropriate packaging container.
The agomelatine film agent prepared according to the prescription and the preparation method has good film forming property, is easy to tear from a substrate film, has smooth appearance and uniform color, and the active ingredient agomelatine crystalline powder particles are uniformly dispersed on the medicine film, and the X-ray powder diffraction measurement shows that the agomelatine is in a crystalline state. In the dissolution test, drug particles are dissolved in a drug film and then are suspended in a dissolution medium after being released, and the dissolution is slow and incomplete.
TABLE 1 dissolution results (Agomelatine in crystalline form)
The agomelatine film prepared in example 1 was compared with agomelatine tablets, and the results of the pharmacokinetic test performed by beagle dogs showed that the bioavailability of the agomelatine film was 2.2 times that of the tablets, and the specific experimental results are shown in example 10.
Meanwhile, ethanol solutions (0-30%) and isopropanol solutions (0-30%) with different concentrations are tested to replace water as solvents, and agomelatine in the prepared film is in a crystalline state and is slowly dissolved out.
Example 2: agomelatine film agent (amorphous film)
According to the preparation method described in example 1, the solvent in the prescription is changed into 50% ethanol solution, agomelatine used in the prescription is in a crystalline form as in example 1, and agomelatine film agent is prepared according to the following prescription, and agomelatine is in an amorphous form in the finally formed film agent.
Prescription:
the agomelatine film prepared according to the prescription and the preparation method has the advantages of smooth appearance, uniform color and no visible crystalline particles on the medicinal film. And (3) the prepared agomelatine film agent shows that the agomelatine is in an amorphous state through X-ray powder diffraction measurement. Meanwhile, the dissolution experiment shows that the medicine is dissolved after the medicine film is dissolved, the dissolution rate can reach 95% after 10 minutes, but then the medicine film is separated out due to the supersaturated part and is reduced to 76%. Thus, the amorphous agomelatine film prepared in this example is superior to the crystalline film described in example 1 in terms of drug dispersion uniformity and dissolution, but is easily re-precipitated due to the low solubility of agomelatine.
Table 2: example 2 dissolution results (agomelatine in amorphous state)
Animal experiments show that the agomelatine film of example 2 has a bioavailability 8.9 times that of oral tablets, and compared with the crystalline film of example 1, the bioavailability is obviously improved, and specific experimental results are shown in example 10.
Example 3: agomelatine film agent (amorphous film + surfactant)
In this example, according to the preparation method described in example 1, the agomelatine film was prepared by adding tween 80 as a surfactant to the formulation of example 2 according to the following formulation, and agomelatine was also in an amorphous state in the final film.
Prescription:
the agomelatine film prepared according to the prescription and the preparation method has the advantages of smooth appearance, uniform color and no visible crystalline particles on the medicinal film. And (3) the prepared agomelatine film agent shows that the agomelatine is in an amorphous state through X-ray powder diffraction measurement. Meanwhile, the dissolution experiment shows that the medicine is dissolved after the medicine film is dissolved, the dissolution rate can reach 98% after 10 minutes, and the medicine can be maintained in a complete dissolution state all the time. Thus prepared surfactant-containing amorphous agomelatine film (example 3) can avoid the problem of recrystallization after drug dissolution, and is superior to the amorphous film described in example 2.
Table 3: example 3 dissolution results (agomelatine in amorphous state)
Animal experiments were carried out on the agomelatine film of example 3, the bioavailability was 12.3 times that of the oral tablet, and compared with the amorphous film without surfactant of example 2, the specific experimental results are shown in example 10.
Meanwhile, an ethanol aqueous solution with the concentration of 40-100%, an isopropanol aqueous solution with the concentration of 40-100%, a dichloromethane aqueous solution with the concentration of 40-100%, an acetone aqueous solution with the concentration of 40-100%, a tertiary butanol aqueous solution with the concentration of 40-100% and film forming materials of different types and proportions, namely hydroxypropyl cellulose, polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, copovidone and polyethylene oxide, are tested, and agomelatine in the prepared film is in an amorphous state, the appearance of the film is uniform, the dissolution is quick, and the recrystallization precipitation is avoided after the dissolution.
Example 4: agomelatine film agent (amorphous film + surfactant + oil phase)
This example was prepared as described in example 1 by adding medium chain triglycerides (Labrafac) to the formulation of example 3 TM lipophile WL 1349, jia farlion), agomelatine films were prepared according to the following formulation, with agomelatine also being in an amorphous state in the final film formed.
Prescription:
the agomelatine film agent prepared according to the prescription and the preparation method shows that the drug film is dissolved, the drug is dissolved after dissolution, but the emulsion state is not successfully formed, the dissolution rate in 10 minutes reaches 97%, and the drug film agent can be maintained in the complete dissolution state all the time. Animal experiments were carried out on the agomelatine film of example 4, with a bioavailability of 11.7 times that of the oral tablet, without significant differences compared to the amorphous film of example 3, the specific experimental results being seen in example 10.
Example 5: agomelatine film agent (amorphous film + surfactant + oil phase, self-emulsifiable)
This example is prepared according to the procedure described in example 1, with the surfactant being replaced by polyethylene glycol glycerol laurate, the oil being replaced by diethylene glycol monoethyl ether, and the agomelatine film being prepared according to the following recipe, the agomelatine being likewise in an amorphous state in the final film formed.
Prescription:
the agomelatine film agent prepared according to the prescription and the preparation method shows that the drug film is dissolved, the drug is dissolved along with the dissolution, the dissolution is in a micro-milky self-emulsifying state after disintegration, the dissolution rate reaches 94% in 10 minutes, and the agomelatine film agent can be kept in a complete dissolution state all the time. Animal experiments were carried out on the agomelatine film of example 5, the bioavailability of the agomelatine film reaches 46.7 times that of the oral tablet, and compared with the amorphous film containing the surfactant of example 3, the bioavailability of the agomelatine film is remarkably improved, and specific experimental results are shown in example 10.
Example 6: agomelatine film agent (amorphous film + surfactant + oil phase)
This example illustrates the preparation of agomelatine films according to the following formulation, which was also amorphous in the final film formed, by testing different oil phase formulations on the formulation of example 5, according to the preparation method described in example 1.
Prescription:
the agomelatine film agent prepared according to the prescription and the preparation method shows that the medicines are dissolved after the films of the examples 6-1 and 6-2 are dissolved, the emulsion state is not successfully formed, the medicines are dissolved after the films of the examples 6-3 and 6-4 are dissolved, and the emulsion state is formed after the medicines are disintegrated.
Agomelatine in the agomelatine films prepared in examples 6-1 to 6-4 were all amorphous.
In this example, oil phases such as medium chain triglyceride, span 80, polyoxyethylene 35 castor oil, glycerol monooleate, diethylene glycol monoethyl ether and oleoyl polyoxyethylene glyceride are also tested, wherein the agomelatine film prepared by using medium chain triglyceride, span 80 and polyoxyethylene 35 castor oil as the oil phases cannot realize self-emulsification, and the agomelatine film prepared by using glycerol monooleate, diethylene glycol monoethyl ether and oleoyl polyoxyethylene glyceride as the oil phases can realize self-emulsification.
Meanwhile, oil phases with different proportions of 1%, 5%, 10%, 15%, 20%, 30% and the like are tested, when the oil phase accounts for 1-20%, agomelatine film agents with good appearance can be obtained after coating and drying are finished, self-emulsification can be realized, when the oil phase accounts for 30%, the film agents after coating and drying are softer and easy to adhere due to the fact that the oil phase accounts for too high oil phase proportion, and the most preferable oil phase proportion is 1-15%.
Example 7: agomelatine film agent (amorphous film + surfactant + oil phase)
This example illustrates the preparation of agomelatine films according to the following formulation, with agomelatine being in an amorphous state in the final film formed, as described in example 1, and the formulations of the different surfactants (emulsifiers) were tested on the formulation of example 5.
Prescription:
the agomelatine film agent prepared according to the prescription and the preparation method shows that the medicines are dissolved after the films of the examples 7-1 and 7-2 are dissolved, the emulsion state is not successfully formed, the medicines are dissolved after the films of the examples 7-3 and 7-4 are dissolved, and the emulsion state is formed after the medicines are disintegrated.
In this example, tween 20, stearic acid, glycerol monostearate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol linoleate and sodium dodecyl sulfate were also tested as surfactants (emulsifiers), wherein the agomelatine film prepared by using tween 20, stearic acid and glycerol monostearate could not achieve self-emulsification, and the agomelatine film prepared by using polyethylene glycol glycerol oleate, polyethylene glycol glycerol linoleate and sodium dodecyl sulfate as surfactants (emulsifiers) could achieve self-emulsification.
Meanwhile, the amounts of surfactants with different proportions of 1%, 5%, 10%, 15%, 20% and the like are tested, when the proportion of the surfactant is 1-15%, agomelatine film with good appearance can be obtained after the coating and drying are finished, self-emulsification can be realized, when the proportion of the surfactant is 20%, self-emulsification cannot be formed due to the fact that the proportion of the surfactant is too high, and the most preferred proportion of the surfactant (emulsifier) is 1-10%.
Example 8: agomelatine film agent (Single film taste)
In this example, the samples obtained in example 5 (single-layer self-emulsifying film) were subjected to taste tests on a plurality of volunteers, and after the film agent attached to the oral mucosa was dissolved, the drug was released, and the volunteers found that the drug had remarkable irritation to the tongue and had poor taste.
In the experiment, a single-layer film is also used for testing a plurality of different types of corrigents (menthol, orange flavor essence, cherry flavor essence, apple flavor essence and the like), sweeteners (sucrose, glucose, saccharin sodium, fructose, xylitol, stevioside, aspartame, sucralose and the like) with different combinations, and different combinations of the sweeteners and the corrigents are also used for masking the taste (such as sucralose, menthol, xylitol, menthol and the like), so that the irritation of agomelatine to the tongue is not obviously improved.
Example 9: agomelatine film agent (double-layer film)
This example was prepared by adding a backing layer to the above example 5 and preparing an agomelatine film bilayer film according to the following formulation.
Prescription:
drug-containing adhesive layer: the agomelatine is completely dissolved in the solvent, and then each component in the prescription is added and stirred until the agomelatine is completely dissolved. Standing or vacuumizing to eliminate bubbles; and (3) uniformly conveying the film forming liquid onto a conveyor belt, drying at 60-90 ℃, volatilizing the solvent in the drying process, and taking out the film after film forming.
A backing layer: except for titanium dioxide (the titanium dioxide should be uniformly dispersed in the film forming liquid), other components in the prescription are added into the solvent in the prescription, stirred until the components are completely dissolved, and then the titanium dioxide is added, stirred and uniformly dispersed. Standing or vacuumizing to eliminate bubbles; uniformly coating the film forming liquid on the dried medicine-containing adhesive layer, drying at 60-90 ℃, volatilizing the solvent in the drying process, cutting into proper size and shape after film forming, and packaging to obtain the agomelatine film agent.
The agomelatine film prepared according to the prescription has good film forming property, smooth appearance and uniform color, the backing layer is white, and the drug-containing adhesive layer is orange.
The samples obtained in this example were tested for mouthfeel on multiple volunteers, with the result that the volunteer response mouthfeel was significantly improved over the single film formulation of example 8, and no irritation to the tongue was perceived throughout the process. The agomelatine film of example 9 was subjected to drug substitution experiments, the bioavailability reached 51.7 times that of the oral tablet, and was significantly higher than that of the oral tablet, and specific experimental results are shown in example 10.
In addition, other different types of backing layer film forming materials, povidone (PVP), polyvinyl alcohol polyethylene glycol copolymer (PVA-PEG), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), cellulose Acetate Phthalate (CAP), hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate (PVAP) and various amounts of 50-100% (w/w) and various backing layer thicknesses (5 μm-100 μm) were tested. Among them, formulations using povidone (PVP), polyvinyl alcohol polyethylene glycol copolymer (PVA-PEG), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO) did not improve the palatability of the formulation. The hydroxypropyl methylcellulose acetate succinate (HPMCAS), the hydroxypropyl methylcellulose (HPMC), the Cellulose Acetate Phthalate (CAP), the hydroxyethyl cellulose (HEC), the polyvinyl alcohol (PVA), the hydroxypropyl methylcellulose phthalate (HPMCP), the polyvinyl alcohol phthalate (PVAP) or the combination thereof is used, and the taste of the prescription can be obviously improved by using 80-100% (w/w). When the thickness of the backing layer is not less than 10 μm and not more than 60 μm, the irritation of the drug is remarkably reduced, when the thickness of the backing layer is less than 10 μm, the irritation masking effect is poor, and when the thickness of the backing layer is more than 60 μm, the effect on the release rate of the drug is large, so that the thickness of the backing layer is preferably 10 to 60 μm, more preferably 10 to 40 μm.
Meanwhile, the formula of the backing layer can be further improved by adding a sweetener and a flavoring agent, such as sucralose, aspartame, saccharin sodium, neotame, acesulfame potassium, menthol, peppermint oil, orange flavor, pineapple flavor, cherry flavor, blueberry flavor and grape flavor, and the content is 0.01-5% w/w, so that the result shows that all the tested sweeteners and flavoring agents can further improve the taste of the formula.
Example 10: bioavailability of agomelatine film
In this example, agomelatine oral tablets (new dimension), examples 1, 2, 3, 4, 5, and 9 were subjected to drug generation tests on beagle dogs. Respectively administering (i) agomelatine film group of example 1, example 2, example 3, example 4, example 5, example 9 with 1mg, and applying to oral mucosa; and (ii) agomelatine tablets, orally administered at a dose of 25mg, were taken at 0.17h,0.33h,0.5h,0.75h,1.0h,1.5h,2.0h,3.0h,4.0h,5.0h,6.0h, respectively, before each dose (0 min) and after each dose, and the agomelatine concentrations in the plasma were determined by LC-MS/MS method, and the relative bioavailability of the prepared films and tablets was calculated, the results are shown in the following table. The oral patches prepared in examples 1 to 5 and 9 had relative bioavailability of 221%, 892%, 1233%, 1167%, 4674% and 5167%, respectively, of the oral tablets, T max 0.75h, 0.5h, 0.33h and 0.39h, respectively, significantly less than the T of an oral tablet max 0.75h, the prepared film agent is administrated through oral mucosa, the absorption speed is obviously faster than that of an oral tablet, and the bioavailability is obviously higher than that of the oral tablet.Wherein in examples 1 and 2, the amorphous film had higher bioavailability than the crystalline film, indicating that the preparation of agomelatine as amorphous film in the formulation improved bioavailability; example 2 the addition of surfactant on an amorphous prescription basis can improve bioavailability compared to example 3; example 3 compared to example 4, the oil phase was added on the basis of the formulation of example 3, but without self-emulsification, there was no significant difference in bioavailability; example 4 compared to example 5 shows that example 5, which is capable of forming self-emulsification, has significantly higher bioavailability than the formulation without self-emulsification; the bioavailability of example 5 and example 9 was not significantly different, but the bilayer film had a significant improvement in mouthfeel.
Results of bioavailability tests for different examples
Note:
the above embodiments are merely illustrative of the principles of the present application and its effectiveness, and are not intended to limit the application. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the application. Accordingly, it is intended that all equivalent modifications and variations of the application be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.

Claims (14)

1. An agomelatine film for oromucosal administration comprising:
(a) A drug-containing adhesive layer: comprises 0.1 to 40 weight parts of amorphous agomelatine or pharmaceutically acceptable salt thereof, 50 to 98 weight parts of first film forming material, 0.5 to 20 weight parts of oil phase and 0.5 to 17 weight parts of surfactant;
(b) A soluble backing layer: comprises 60-100 parts by weight of a second film forming material;
the first film forming material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, povidone and polyethylene oxide;
the second film forming material is one or more of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, cellulose acetate phthalate, hydroxyethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose phthalate and polyvinyl alcohol phthalate;
the oil phase is one or more of propylene glycol dicaprate, glycerol monolinoleate, glycerol monooleate, diethylene glycol monoethyl ether, oleoyl polyoxyethylene glyceride, propylene glycol laurate, polyglycerol-4 oleate, isooctyl palmitate, polyethylene glycol cetostearyl ether and polyglycerol-3-diisostearate;
the surfactant is one or more of lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride, oleic acid polyethylene glycol glyceride, linoleic acid polyethylene glycol glyceride, sodium dodecyl sulfate, monocaprylic acid capric acid glyceride, polyethylene glycol-32 stearate, caprylic acid capric acid polyethylene glycol glyceride and 15-hydroxystearic acid polyethylene glycol ester.
2. Agomelatine film according to claim 1, characterised in that the backing layer has a thickness of 10-60 μm.
3. Agomelatine film according to claim 1, characterised in that: the medicated adhesion layer comprises 0.5% -25% by weight agomelatine.
4. Agomelatine film according to claim 1, characterised in that: the medicated adhesive layer may also comprise one or more sweeteners and one or more flavoring agents.
5. Agomelatine film according to claim 1, characterised in that: the backing layer may also comprise one or more sweeteners and one or more flavoring agents.
6. Agomelatine film according to claim 1, characterised in that: the drug-containing adhesive layer comprises 0.5-25% by weight of agomelatine or pharmaceutically acceptable salt thereof, 70-95% by weight of a first film forming material, 1-20% by weight of an oil phase and 1-15% by weight of a surfactant-emulsifier.
7. Agomelatine film according to claim 6, characterised in that: the drug-containing adhesive layer contains 0.1-10mg of amorphous agomelatine.
8. Agomelatine film according to claim 1, characterised in that: the drug-containing adhesive layer may further comprise an adhesive agent that improves the adhesion of the film agent in the oral mucosa.
9. Agomelatine film according to claim 1, prepared in the following manner:
(a) Adding agomelatine or a pharmaceutically acceptable salt thereof, a film-forming material, an oil phase and a surfactant to a first composition
Preparing a film forming solution containing the medicine in an aqueous solution of an organic solvent;
(b) Uniformly coating and drying the film forming liquid of the medicine-containing adhesive layer to form a film, thereby obtaining the medicine-containing adhesive layer;
(c) Adding the second film forming material into water or a second aqueous solution containing an organic solvent to prepare backing layer film forming liquid;
(d) Uniformly coating the film forming solution of the backing layer on the prepared medicine-containing adhesive layer, and drying to form a film to obtain the backing layer and the medicine-containing adhesive layer
A bilayer film comprising a drug-containing adhesive layer.
10. The agomelatine film preparation method according to claim 9, characterized in that: (a) Wherein the concentration of the organic solvent in the first aqueous solution containing the organic solvent is 40% to 100% w/w; the organic solvent is one or more mixed liquid of ethanol, isopropanol, acetone, tertiary butanol and methylene dichloride.
11. The agomelatine film preparation method according to claim 10, characterized in that: the organic solvent is ethanol.
12. An agomelatine film agent for oral mucosa administration is characterized by comprising a medicine-containing adhesive layer, wherein the medicine-containing adhesive layer comprises 0.1-40 parts by weight of amorphous agomelatine or pharmaceutically acceptable salt thereof, 50-98 parts by weight of a first film forming material, 0.5-20 parts by weight of an oil phase and 0.5-17 parts by weight of a surfactant;
the oil phase is one or more of propylene glycol dicaprate, glycerol monolinoleate, glycerol monooleate, diethylene glycol monoethyl ether, oleoyl polyoxyethylene glyceride, propylene glycol laurate, polyglycerol-4 oleate, isooctyl palmitate, polyethylene glycol cetostearyl ether and polyglycerol-3-diisostearate;
the surfactant is one or more of lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride, oleic acid polyethylene glycol glyceride, linoleic acid polyethylene glycol glyceride, sodium dodecyl sulfate, monocaprylic acid capric acid glyceride, polyethylene glycol-32 stearate, caprylic acid capric acid polyethylene glycol glyceride and 15-hydroxystearic acid polyethylene glycol ester.
13. The oromucosal agomelatine film according to claim 12, characterised in that it further comprises:
a soluble backing layer: comprising 60-100 parts by weight of a second film forming material.
14. The agomelatine film agent for oral mucosa administration according to claim 13, characterized in that the first film forming material is one or more of hypromellose, hydroxypropyl cellulose, polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, povidone, polyethylene oxide;
the second film forming material is one or more of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, cellulose acetate phthalate, hydroxyethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose phthalate and polyvinyl alcohol phthalate.
CN202311054277.8A 2023-08-21 2023-08-21 Agomelatine film agent for oral mucosa administration and preparation method thereof Pending CN116832015A (en)

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